[Severe Conjunctival and Corneal Epithelial Dysplasia: A Case Series]. / Schwere konjunktivale und korneale epitheliale Dysplasie: eine Fallserie.

BACKGROUND/OBJECTIVES: Ocular surface squamous neoplasia (OSSN) are among the most frequent non-pigmented malignancies of the ocular surface. They have a wide range of histological characteristics - ranging from mild epithelial dysplasia to invasive carcinoma of the squamous cells of the cornea. They may be restricted to the conjunctiva or also involve the cornea. As there are no leading symptoms in the early stages, diagnosis may be very delayed in patients who do not receive regular ophthalmological treatment. The present case series describes clinical and histological data on OSSN and includes clinical and histological data on OSSN, including possible clinical presentations, important risk factors, special histological and cytological features and therapeutic options. METHODS: Retrospective case series of patients with histologically confirmed severe epithelial dysplasia of the conjunctiva and cornea consistent with OSSN who presented to the Department of Ophthalmology in Basel University Hospital. The analysis covered demographic data, symptoms, diagnostic testing (photo documentation, brush biopsy), treatment and cytological and/or histological material and findings. RESULTS: We report on five patients aged between 41 and 92 years at the time of diagnosis. The histological findings in all patients included severe epithelial dysplasia, but with a heterogenous clinical presentation. In all cases, the lesion started in the conjunctiva, but traversed the limbus and extended to the cornea. The primary treatment was always surgical removal. In one patient, this had to be repeated several times due to recurrent metaplasia and was complemented by subsequent mitomycin C therapy. The clinical outcome ranged between total restitution of the original state to inevitable enucleation. CONCLUSION: The clinical presentation of OSSN is highly heterogenous, so that the initial diagnosis is difficult. There are no official guidelines for treatment, so that the treatment of choice varied between clinics. Regular ophthalmological follow-ups are recommended, even after complete surgical excision. Possible relevant concomitant diseases and risk factors must be identified before therapy.

The Pediatric and Young Adult Choroidal and Ciliary Body Melanoma Genetic Study, A Survey by the European Ophthalmic Oncology Group.

Purpose: To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group. Methods: Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor. Next-generation sequencing using Ion Torrent platform was used to determine pathogenic variants of BAP1, EIF1AX, SF3B1, GNAQ and GNA11 and chromosome 3 status in the tumor or in DNA extracted from blood or saliva. Survival was analyzed using Kaplan-Meier estimates. Results: The mean age at diagnosis was 17 years (range 5.0-24.8). A germline BAP1 pathogenic variant was identified in an 18-year-old patient, and a somatic variant, based mainly on immunohistochemistry, in 13 (42%) of 31 available specimens. One tumor had a somatic SF3B1 pathogenic variant. Disomy 3 and the absence of a BAP1 pathogenic variant in the tumor predicted the longest metastasis-free survival. Males showed longer metastasis-free survival than females (P = 0.018). Conclusions: We did not find a stronger-than-average BAP1 germline predisposition for choroidal and ciliary body melanoma among children and young adults compared to adults. Males had a more favorable survival and disomy 3, and the absence of a BAP1 mutation in the tumor tissue predicted the most favorable metastasis-free survival. A BAP1 germline pathogenic variant was identified in one patient (1%), and a somatic variant based mainly on immunohistochemistry in 13 (42%).

Adaptive monitoring in action-what drives arthropod diversity and composition in central European beech forests?

Recent studies suggest that arthropod diversity in German forests is declining. Currently, different national programs are being developed to monitor arthropod trends and to unravel the effects of forest management on biodiversity in forests. To establish effective long-term monitoring programs, a set of drivers of arthropod diversity and composition as well as suitable species groups have to be identified. To aid in answering these questions, we investigated arthropod data collected in four Hessian forest reserves (FR) in the 1990s. To fully utilize this data set, we combined it with results from a retrospective structural sampling design applied at the original trap locations in central European beech (Fagus sylvatica) forests. As expected, the importance of the different forest structural, vegetation, and site attributes differed largely between the investigated arthropod groups: beetles, spiders, Aculeata, and true bugs. Measures related to light availability and temperature such as canopy cover or potential radiation were important to all groups affecting either richness, composition, or both. Spiders and true bugs were affected by the broadest range of explanatory variables, which makes them a good choice for monitoring general trends. For targeted monitoring focused on forestry-related effects on biodiversity, rove and ground beetles seem more suitable. Both groups were driven by a narrower, more management-related set of variables. Most importantly, our study approach shows that it is possible to utilize older biodiversity survey data. Although, in our case, there are strong restrictions due to the long time between species and structural attribute sampling.

A large quantitative analysis of written language challenges the idea that all languages are equally complex.

One of the fundamental questions about human language is whether all languages are equally complex. Here, we approach this question from an information-theoretic perspective. We present a large scale quantitative cross-linguistic analysis of written language by training a language model on more than 6500 different documents as represented in 41 multilingual text collections consisting of ~ 3.5 billion words or ~ 9.0 billion characters and covering 2069 different languages that are spoken as a native language by more than 90% of the world population. We statistically infer the entropy of each language model as an index of what we call average prediction complexity. We compare complexity rankings across corpora and show that a language that tends to be more complex than another language in one corpus also tends to be more complex in another corpus. In addition, we show that speaker population size predicts entropy. We argue that both results constitute evidence against the equi-complexity hypothesis from an information-theoretic perspective.

Determination of aquatic hazard concentrations for the oil spill response product class of surface washing agents using species sensitivity distributions.

Surface washing agents (SWAs) are a diverse class of oil spill response products intended to facilitate removal of stranded oil from shorelines. This class of agents has high application rates relative to other categories of spill response products, but global toxicity data is generally limited to two standard test species: inland silverside and mysid shrimp. Here, we provide a framework to maximize the utility of limited toxicity data across a product class. To characterize species sensitivity to SWAs, the toxicity of three agents spanning a range of chemical and physical properties were tested in eight species. The relative sensitivity of mysids shrimp and inland silversides as surrogate test organisms was determined. Toxicity normalized species sensitivity distributions (SSDn) were used to estimate fifth centile hazard concentration (HC5) values for SWAs with limited toxicity data. Chemical toxicity distributions (CTD) of SWA HC5 values were used to compute a fifth centile chemical hazard distribution (HD5) to provide a more comprehensive assessment of hazard across a spill response product class with limited toxicity data than traditional single species or single agent approaches can give.

674 Cases of Late Postoperative Intraocular Lens Opacification of a Hydrophilic-Hydrophobic Acryl Intraocular Lens in Switzerland and Retrospective Opacification Risk Factor Assessment of 212 Cases.

PURPOSE: To report the prevalence of late postoperative opacification of a hydrophilic and hydrophobic acrylic intraocular lens (IOL) and to assess the risk factors in a subset of 212 eyes of patients referred to the University Eye Department in Basel, Switzerland. DESIGN: Retrospective case series. METHODS: A survey was performed at all large ophthalmological clinics in Switzerland regarding exchanged Lentis LS-502-1 lenses, and the number of affected eyes was counted. Moreover, consecutive patients who were referred to a tertiary clinic between September 2015 and November 2016 with Lentis LS-502-1 opacification were investigated. Peri- and postoperative charts, medical history, and topical and systemic medications were assessed. RESULTS: A total of 674 opacified Lentis LS-502-1 lenses have been reported in Switzerland, and 212 consecutive eyes of 182 patients were included in the study. All IOLs had a similar pattern of opacification with a yellowish, diffuse appearance, and most of them showed a small, paracentral, roundish area that was less affected or not at all. Arterial hypertension (73%), hypercholesterolemia (34%), and diabetes (21%) were the main associated systemic diseases, and statins (34%) and betablockers (34%) were the main treatments used. CONCLUSIONS: The prevalence of IOL opacification was 9.9%. No associated systemic eye disease or medications could be detected, which was implicated in the opacification process. The reason for opacification remains unclear, but it seems to be unrelated to the patient's state; therefore, it is attributed to primary calcification.

Pembrolizumab-induced optic neuropathy - a case report.

Background: Immune checkpoint inhibitor (ICI) treatment has become important for treating various cancer types, including Hodgkin's lymphoma. However, ICI can overstimulate the immune system, leading to a broad range of immunological side effects, known as immune-related adverse events (irAEs). Here, we report a case of optic neuropathy caused by pembrolizumab. Case presentation: A patient with Hodgkin's lymphoma received pembrolizumab every three weeks. Twelve days after the sixth cycle of pembrolizumab, the patient was admitted to the emergency department with blurred vision, visual field impairment and altered color perception affecting the right eye. The diagnosis of immune-related optic neuropathy was established. Pembrolizumab was stopped permanently and high-dose steroid treatment was immediately started. This emergency treatment led to a satisfactory binocular vision and an improvement of visual acuity testing results. After another 7 months, the left eye was affected with the same symptoms. At this time, only an extended immunosuppressive therapy consisting of high-dose steroid treatment, plasmapheresis, immunoglobulin treatment, retrobulbar injection of steroids and mycophenolate mofetil, successfully reduced the symptoms. Conclusions: This case highlights the need for prompt recognition and treatment of rare irAEs, such as optic neuropathy. Urgent treatment with initial high-dose steroid treatment is required to avoid persistent loss of visual acuity. Options for further treatment are mainly based on small case series and case reports. In our case, a retrobulbar injection of steroids in combination with mycophenolate mofetil showed significant success in treating steroid-refractory optic neuropathy.

Clinical, histopathological and molecular features of dedifferentiated melanomas: An EORTC Melanoma Group Retrospective Analysis.

PURPOSE: Dedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) and copy number profiling (CNP) were carried out in a subgroup of cases. PATIENTS AND METHODS: A retrospective series of 78 DedM tissue samples from 61 patients retrieved from EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group centres were centrally reviewed. Clinical and histopathological features were retrieved. In a subgroup of patients, genotyping through Infinium Methylation microarray and CNP analysis was carried out. RESULTS: Most patients (60/61) had a metastatic DedM showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin to undifferentiated soft tissue sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed tissue samples from 16 patients, we found retained melanoma-like MS in only 7 tissue samples while a non-melanoma-like MS was observed in 13 tissue samples. In two patients from whom multiple specimens were analysed, some of the samples had a preserved cutaneous melanoma MS while other specimens exhibited an epigenetic shift towards a mesenchymal/sarcoma-like profile, matching the histological features. In these two patients, CNP was largely identical across all analysed specimens, in line with their common clonal origin, despite significant modification of their epigenome. CONCLUSIONS: Our study further highlights that DedM represents a real diagnostic challenge. While MS and genomic CNP may help pathologists to diagnose DedM, we provide proof-of-concept that dedifferentiation in melanoma is frequently associated with epigenetic modifications.

The Geriatric Prognostic Index: a clinical prediction model for survival of older diffuse large B-cell lymphoma patients treated with standard immunochemotherapy.

The International prognostic Index (IPI) is the most widely used clinical prediction model for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but may be suboptimal in older patients. We aimed to develop and externally validate a clinical prediction model for older, RCHOP- treated DLBCL patients by examining geriatric assessment and lymphoma-related parameters in real-world cohorts. A population-based training set of 365 R-CHOP-treated DLBCL patients ≥70 years was identified through the Cancer Registry of Norway. The external test set consisted of a population-based cohort of 193 patients. Data on candidate predictors were retrieved from the Cancer Registry and through review of clinical records. Cox regression models for 2-year overall survival were used for model selection. Activities of daily living, the Charlson Comorbidity Index, age, sex, albumin, stage, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level were identified as independent predictors and combined into a Geriatric Prognostic Index (GPI). The GPI demonstrated good discrimination (optimismcorrected C-index 0.752), and identified low-, intermediate- and high-risk groups with significantly different survivals (2- year overall survival, 94%, 65%, and 25%, respectively). At external validation, the continuous and grouped GPI demonstrated good discrimination (C-index 0.727 and 0.710, respectively) and the GPI groups had significantly different survivals (2-year overall survival 95%, 65%, and 44%, respectively). Both the continuous and grouped GPI showed better discrimination than the IPI, revised-IPI and National Comprehensive Cancer Network (NCCN)-IPI (C-index 0.621, 0.583, and 0.670, respectively). In conclusion, we have developed and externally validated a GPI for older DLBCL patients treated with R-CHOP that outperformed the IPI, revised-IPI and NCCN-IPI. A web-based calculator is available at https://wide.shinyapps. io/GPIcalculator/.

Large-scale morphometry of the subarachnoid space of the optic nerve.

BACKGROUND: The meninges, formed by dura, arachnoid and pia mater, cover the central nervous system and provide important barrier functions. Located between arachnoid and pia mater, the cerebrospinal fluid (CSF)-filled subarachnoid space (SAS) features a variety of trabeculae, septae and pillars. Like the arachnoid and the pia mater, these structures are covered with leptomeningeal or meningothelial cells (MECs) that form a barrier between CSF and the parenchyma of the optic nerve (ON). MECs contribute to the CSF proteome through extensive protein secretion. In vitro, they were shown to phagocytose potentially toxic proteins, such as α-synuclein and amyloid beta, as well as apoptotic cell bodies. They therefore may contribute to CSF homeostasis in the SAS as a functional exchange surface. Determining the total area of the SAS covered by these cells that are in direct contact with CSF is thus important for estimating their potential contribution to CSF homeostasis. METHODS: Using synchrotron radiation-based micro-computed tomography (SRµCT), two 0.75 mm-thick sections of a human optic nerve were acquired at a resolution of 0.325 µm/pixel, producing images of multiple terabytes capturing the geometrical details of the CSF space. Special-purpose supercomputing techniques were employed to obtain a pixel-accurate morphometric description of the trabeculae and estimate internal volume and surface area of the ON SAS. RESULTS: In the bulbar segment, the ON SAS microstructure is shown to amplify the MECs surface area up to 4.85-fold compared to an "empty" ON SAS, while just occupying 35% of the volume. In the intraorbital segment, the microstructure occupies 35% of the volume and amplifies the ON SAS area 3.24-fold. CONCLUSIONS: We provided for the first time an estimation of the interface area between CSF and MECs. This area is of importance for estimating a potential contribution of MECs on CSF homeostasis.

[Ocular alterations in patients with Alport syndrome-An update]. / Okuläre Veränderungen bei Patienten mit Alport-Syndrom ­ ein Update.

BACKGROUND AND OBJECTIVE: Alport syndrome (AS) is a rare hereditary systemic disease that results in alterations of the kidneys, inner ear, and various structures of the eye. It is caused by mutations in one of the genes encoding collagen type IV. In recent years, new and innovative imaging techniques have added characteristics of ocular alterations in AS and provided new insights, including into the pathogenesis of the disease. The aim of this paper is to provide an overview of the current knowledge of ocular changes in AS, as well as to present the Alport ocular pass. METHOD: Narrative review article. RESULTS: Ocular manifestations of AS include changes in the cornea, lens, and retina. Specifically, posterior polymorphic corneal dystrophy, anterior lenticonus (pathognomonic for AS), and various retinal changes have been described, which have been further characterized in recent years by newer imaging techniques. In particular, foveal changes in AS may present as both a thickened central retina in the context of foveal hypoplasia or a staircase-like thinning of the fovea. Both lesions could provide further insights into the role of type IV collagen in ocular structures. CONCLUSION: The AS can manifest in various structures of the eye. The staircase-like changes of the central retina in AS patients indicate the important role of collagen type IV in the homeostasis and regular function of the inner retinal layers. The often mild foveal hypoplasia may provide clues to the role of collagen type IV in retinal embryogenesis. While anterior lenticonus is pathognomonic for AS and can be treated easily by refractive lens exchange, the only option currently available for retinal alterations is close follow-up and, if necessary, treatment of systemic complications of AS.

RGD Peptidomimetic MMAE-Conjugate Addressing Integrin αVß3-Expressing Cells with High Targeting Index.

Small molecule-drug conjugates (SMDCs) mimicking the RGD sequence (-Arg-Gly-Asp-) with a non-peptide moiety require a pharmacophore-independent attachment site. A library of 36 sulfonamide-modified RGD mimetics with nM to pM affinity for integrin αV ß3 was synthesized and analysed via DAD mapping. The best structure of the conjugable RGD mimetic was used and a linker was attached to an aromatic ring by Negishi cross-coupling. The product retained high affinity and selectivity for integrin αV ß3 . The conjugable RGD mimetic was then attached to an enzymatically cleavable GKGEVA linker equipped with a self-immolative PABC and the antimitotic drug monomethyl auristatin E (MMAE). The resulting SMDC preferred binding to integrin αV ß3 over α5 ß1 in a ratio of 1 : 4519 (ELISA) and showed selectivity for αV ß3 -positive WM115 cells over αV ß3 -negative M21-L cells in the in vitro cell adhesion assay as well as in cell viability assays with a targeting index of 134 (M21-L/WM115).

Validation of the Dutch translation of the quality of recovery-15 scale.

BACKGROUND: The 15-item Quality of Recovery-15 (QoR-15) scale is strongly recommended as a standard patient-reported outcome measure assessing the quality of recovery after surgery and anesthesia in the postoperative period. This study aimed to validate the Dutch translation of the questionnaire (QoR-15NL). MATERIALS AND METHODS: An observational, prospective, single-centre cohort study was conducted. Patients who underwent surgery under general anesthesia completed the QoR-15NL (preoperatively (t1) and twice postoperatively (t2 and t3)) and a visual analogue scale (VAS) for general recovery at t2. A psychometric evaluation was performed to assess the QoR-15NL's validity, reliability, responsiveness, reproducibility and feasibility. RESULTS: Two hundred and eleven patients agreed to participate (recruitment rate 94%), and 165 patients were included (completion rate 78%). The QoR-15NL score correlated with the VAS for general recovery (rs = 0.59). Construct validity was further demonstrated by confirmation of expected negative associations between the QoR-15NL and duration of surgery (rs = -0.25), duration of Post Anesthesia Care Unit stay (rs = -0.31), and duration of hospital stay (rs = -0.27). The QoR-15NL score decreased significantly according to the extent of surgery. Cronbach's alpha was 0.87, split-half reliability was 0.8, and the test-retest intra-class coefficient was 0.93. No significant floor- or ceiling effect was observed. CONCLUSION: The QoR-15NL scale is a valid, easy-to-use, and reliable outcome assessment tool with high responsiveness for patient-reported quality of recovery after surgery and general anesthesia in the Dutch-speaking population. The QoR-15NL's measurement properties are comparable to the original questionnaire and other translated versions. TRIAL REGISTRATION: not applicable.

Congenital orbital teratoma: A clinicopathologic case report.

PURPOSE: Orbital teratoma can be removed in order to preserve the bulb. OBSERVATIONS: Case report of a newborn with an orbital tumor. After spontaneous birth, a massive bulbus protrusion on the left side was observed. Magnetic Resonance Imaging (MRI) diagnosis showed an intraorbital cystic lesion containing solid parts and displacing the bulbus oculi. Suspecting a teratoma, primarily a cystic puncture was performed on the first day of life. On the 3rd day of life, cystic lesion was completely resected while preserving the bulbus. Histologically a mature cystic teratoma was observed. CONCLUSION AND IMPORTANCE: This case shows how important prenatal diagnostics is in order to plan the necessary birth preparations in advance and that a bulbus-preserving surgery in orbital teratoma is possible. In the absence of yolk-salk tumor it is associated with a good prognosis.

Rituximab-treated patients with lymphoma develop strong CD8 T-cell responses following COVID-19 vaccination.

B-cell depletion induced by anti-cluster of differentiation 20 (CD20) monoclonal antibody (mAb) therapy of patients with lymphoma is expected to impair humoral responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, but effects on CD8 T-cell responses are unknown. Here, we investigated humoral and CD8 T-cell responses following two vaccinations in patients with lymphoma undergoing anti-CD20-mAb therapy as single agent or in combination with chemotherapy or other anti-neoplastic agents during the last 9 months prior to inclusion, and in healthy age-matched blood donors. Antibody measurements showed that seven of 110 patients had antibodies to the receptor-binding domain of the SARS-CoV-2 Spike protein 3-6 weeks after the second dose of vaccination. Peripheral blood CD8 T-cell responses against prevalent human leucocyte antigen (HLA) class I SARS-CoV-2 epitopes were determined by peptide-HLA multimer analysis. Strong CD8 T-cell responses were observed in samples from 20/29 patients (69%) and 12/16 (75%) controls, with similar median response magnitudes in the groups and some of the strongest responses observed in patients. We conclude that despite the absence of humoral immune responses in fully SARS-CoV-2-vaccinated, anti-CD20-treated patients with lymphoma, their CD8 T-cell responses reach similar frequencies and magnitudes as for controls. Patients with lymphoma on B-cell depleting therapies are thus likely to benefit from current coronavirus disease 2019 (COVID-19) vaccines, and development of vaccines aimed at eliciting T-cell responses to non-Spike epitopes might provide improved protection.

Comparative Toxicity of Oil Spill Herding Agents to Aquatic Species.

Chemical herding agents are surfactant mixtures used to coalesce spilled oil and increase slick thickness to facilitate mechanical recovery or in situ burning. Only two herders are currently listed on the United States' National Oil and Hazardous Substances Pollution Contingency Plan or National Contingency Plan product schedule for potential use in spill response: the surface collecting agents Siltech OP-40™ and ThickSlick 6535™. Toxicity data for spill response agents are frequently available only for two estuarine species, mysid shrimp (Americamysis bahia) and inland silversides (Menidia beryllina), and are particularly limited for herding agents. Toxicity can vary over several orders of magnitude across product type and species, even within specific categories of spill response agents. Seven aquatic species were tested with both Siltech OP-40™ and ThickSlick 6535™ to evaluate acute herder toxicity and relative species sensitivity. The toxicity assessment included: acute tests with A. bahia and M. beryllina, the freshwater crustacean Ceriodaphina dubia, and the freshwater fish Pimephales promelas; development of the echinoderm Arbacia unctulate; and growth of a freshwater alga Raphidocelis subcapitata and marine alga Dunaliella tertiolecta. Siltech acute toxicity values ranged from 1.1 to 32.8 ppm. ThickSlick acute toxicity values ranged from 2.2 to 126.4 ppm. The results of present study show greater toxicity of Siltech compared to ThickSlick with estimated acute hazard concentrations intended to provide 95% species protection of 1.1 and 3.6 ppm, respectively, on empirical data and 0.64 and 3.3 ppm, respectively, with the addition of interspecies correlation data. The present study provides a greater understanding of species sensitivity of these two oil spill response agents. Environ Toxicol Chem 2022;41:1311-1318. © 2022 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.